Immune checkpoint therapy in colorectal cancer: is first better than last?

Yui Kaneko; Zainab Naseem; Neil Strugnell; Frances Barnett; Basil D’Souza; Ankur Sidhu; Andrew Bui; Toan Pham

doi:10.3393/ac.2023.00248.0035

Articles

Page Path: HOME > Ann Coloproctol > Volume 39(5); 2023 > Article

Brief Communication Colorectal cancer Immune checkpoint therapy in colorectal cancer: is first better than last?: Yui Kaneko¹, Zainab Naseem¹, Neil Strugnell¹, Frances Barnett², Basil D’Souza¹, Ankur Sidhu¹, Andrew Bui^1,3, Toan Pham^1,4; Annals of Coloproctology 2023;39(5):439-441.
DOI: https://doi.org/10.3393/ac.2023.00248.0035
Published online: October 4, 2023

¹Division of General Surgery, Colorectal Unit, Northern Hospital Epping, Melbourne, VIC, Australia

²Division of Medical Oncology, Northern Hospital Epping, Melbourne, VIC, Australia

³Division of General Surgery, Colorectal Unit, Austin Hospital, Melbourne, VIC, Australia

⁴Division of Surgery, Colorectal Unit, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Correspondence to: Yui Kaneko, BMedSci (Hons), PhD, MD, FRACS Division of General Surgery, Colorectal Unit, Northern Hospital Epping, 185 Cooper St Epping, Melbourne, VIC 3076, Australia Email: Yui.kaneko2@nh.org.au

• Received: March 29, 2023 • Revised: May 18, 2023 • Accepted: May 21, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

prev next

5,815 Views
114 Download
1 Web of Science
1 Crossref
1 Scopus

Full Article

Download PDF

ARTICLE INFORMATION
REFERENCES

Immunotherapy advances involving checkpoint inhibitors have revolutionized treatment for various cancers. In colorectal cancer (CRC), the application of immune checkpoint inhibitors (ICIs) is well-established for metastatic or unresectable microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) disease. However, the role of ICIs in the neoadjuvant setting has yet to be determined. The question remains: can neoadjuvant immunotherapy alter the management of MSI-H/dMMR CRCs in the future?

Let us first summarize how MSI-H/dMMR CRC is well-suited for ICI therapy. The dMMR CRC cells typically have higher mutational burdens than their mismatch repair-proficient (pMMR) counterparts [1]. This results in more non–self-proteins being produced and displayed on the cell surface, making them more likely to be recognized by the body’s immune system as foreign or a so-called hot cancer. Consequently, a cytotoxic response is triggered to eliminate these cells. Unfortunately, cancer evolution has enabled malignant cells to exploit a fail-safe signal employed by healthy cells to subdue aberrant autoimmune attacks by upregulating inhibitory ligands for 2 immune checkpoint receptors (ICRs)—programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)—found on immune cells. As a result, when a cytotoxic lymphocyte attempts to destroy these cancer cells, it is inhibited. The groundbreaking discovery of these ligands was acknowledged when the 2018 Nobel Prize in Physiology or Medicine was awarded to Professors Tasuku Honjo and James Allison for their work on PD-1 and CTLA-4, respectively [2].

ICI therapy with pembrolizumab is currently approved for metastatic MSI-H/dMMR CRC. The pivotal study leading to this indication was the KEYNOTE-177 Trial [3], which demonstrated that pembrolizumab was associated with a superior overall response rate compared to standard chemotherapy (43.8% vs. 33.1%) in metastatic MSI-H/dMMR CRC. In the final analysis, the superiority of pembrolizumab over chemotherapy for overall survival was not demonstrated. However, at a median follow-up of 44.5 months, a trend was observed towards improved survival, with median overall survival not reached with pembrolizumab treatment versus 36.7 months with chemotherapy (hazard ratio, 0.74; 95% confidence interval, 0.53–1.03; P=0.036) [4]. Importantly, the pembrolizumab group experienced fewer serious treatment-related adverse events than the chemotherapy group [4]. That study supports pembrolizumab as an effective therapy for patients with metastatic MSI-H/dMMR CRC.

In 2017, the US Food and Drug Administration (FDA) approved pembrolizumab for the treatment of patients with unresectable or metastatic MSI-H or dMMR solid tumors, including CRCs, that had progressed after chemotherapy treatment. The following year, the FDA approved nivolumab, either alone or in combination with ipilimumab, for patients with MSI-H/dMMR that progresses after standard chemotherapy [5].

Recent studies of stage III melanoma have demonstrated promising results for ICIs in the neoadjuvant setting relative to adjuvant therapy [6, 7]. The neoadjuvant administration of immunotherapy offers a window of opportunity to elicit a stronger and broader tumor-specific T-cell response than would be expected in the adjuvant setting. Furthermore, importantly, ICIs are most effective when a demonstrable antigen load is present, as with metastatic disease or when administered in a neoadjuvant setting with cancer in situ [7, 8]. Neoadjuvant immunotherapy also has been and/or is currently being evaluated in the contexts of many other cancers, including CRC, with promising clinical trial data available. In the NICHE Trial [8], researchers assessed the efficacy of neoadjuvant immunotherapy in pMMR and dMMR stage I to III colon cancer. Initial results were encouraging, with neoadjuvant treatment of early-stage colon cancer using a single dose of ipilimumab and 2 doses of nivolumab achieving degrees of pathological response in all dMMR tumors (including pathologic complete response in 12 of 20 cases) and in 4 of 15 pMMR tumors. The immunotherapy was well tolerated, with only 13% of patients experiencing grade 3 to 4 immune-related toxicities, and importantly, it did not compromise planned surgery in any patient. The NICHE-2 study group further investigated dMMR colon cancer; preliminary results validated their previous trial, with a major pathologic response rate (defined as <10% residual tumor) of 95% and a complete pathological response rate of 67% [9].

Similarly, the PICC (PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer) Trial [10] was a single-center randomized clinical trial conducted in China, in which 34 patients with MSI-H/dMMR locally advanced colorectal cancer received neoadjuvant toripalimab, either alone or in combination with celecoxib, prior to surgical resection. The preliminary results showed high pathological complete response rates of 88% in the toripalimab plus celecoxib group and 65% in the toripalimab monotherapy group, which is consistent with the results of the NICHE-1 and NICHE-2 trials.

Additionally, 2 clinical trials have demonstrated complete response from neoadjuvant immunotherapy [11, 12]. A retrospective multicenter study in China [11] included 73 patients with localized dMMR CRC who received PD-1 inhibitors as neoadjuvant therapy. Of these patients, 23 did not proceed to surgery, and 17 of these experienced a complete radiological response. The reported 2-year tumor-specific disease-free survival and overall survival rates were both 100%. The other trial was a prospective phase 2 study conducted at the Memorial Sloan Kettering Cancer Center (New York, NY, USA) [12], in which single-agent dostarlimab was administered as neoadjuvant therapy in cases of dMMR stage II or III rectal adenocarcinoma. A total of 12 patients completed treatment with dostarlimab monotherapy, achieving a 100% clinical complete response and no evidence of recurrence after at least 6 months of follow-up without chemoradiation or surgery. No significant adverse events were reported.

Neoadjuvant immunotherapy is a rapidly developing area in the treatment of MSI-H/dMMR CRC. A substantial proportion of these patients have Lynch syndrome; as such, they tend to be younger, meaning that preservation of fertility, sexual function, and bowel function is particularly important. If immunotherapy is shown to have long-term efficacy and safety, it may be possible to avoid the traditional therapeutic modalities for rectal cancer of surgery, chemotherapy, and radiotherapy, potentially leading to a significantly improved quality of life compared to current treatments [13]. From a practical standpoint, MMR status testing must be routinely requested on preoperative biopsies from patients with newly diagnosed CRC.

Now is an opportune time to establish additional clinical trials to validate the findings of international studies, assess local feasibility, identify the most effective treatment and duration, and correlate the pathological response with disease-free and overall survivals. The current data are promising, suggesting that neoadjuvant immunotherapy could become the first-line therapy or standard of care in MSI-H/dMMR CRC. However, the existing evidence relies on preliminary findings from limited clinical trials, due to the relatively low prevalence of MSI-H/dMMR among CRC cases. Hence, more research is required to validate long-term efficacy and safety in this patient population.

ARTICLE INFORMATION

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization: all authors; Writing–original draft: YK, Writing–review & editing: all authors. All authors read and approved the final manuscript. All authors contributed to the work and read and approved the final manuscript.

REFERENCES

1. Olave MC, Graham RP. Mismatch repair deficiency: the what, how and why it is important. Genes Chromosomes Cancer 2022;61:314–21.Article PubMed PDF
2. Huang PW, Chang JW. Immune checkpoint inhibitors win the 2018 Nobel Prize. Biomed J 2019;42:299–306.Article PubMed PMC
3. André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383:2207–18.Article PubMed
4. Diaz LA Jr, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol 2022;23:659–70.Article PubMed PMC
5. Chang L, Chang M, Chang HM, Chang F. Microsatellite instability: a predictive biomarker for cancer immunotherapy. Appl Immunohistochem Mol Morphol 2018;26:e15–21.Article PubMed
6. van Akkooi AC, Blank C, Eggermont AM. Neo-adjuvant immunotherapy emerges as best medical practice, and will be the new standard of care for macroscopic stage III melanoma. Eur J Cancer 2023;182:38–42.Article PubMed
7. Blank CU, Rozeman EA, Fanchi LF, Sikorska K, van de Wiel B, Kvistborg P, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018;24:1655–61.Article PubMed PDF
8. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020;26:566–76.Article PubMed PDF
9. Chalabi M, Verschoor YL, van den Berg J, Sikorska K, Beets G, Lent AV, et al. LBA7 neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: the NICHE-2 study. Ann Oncol 2022;33:S1389. Article
10. Hu H, Kang L, Zhang J, Wu Z, Wang H, Huang M, et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2022;7:38–48.Article PubMed
11. Xiao BY, Zhang X, Cao TY, Li DD, Jiang W, Kong LH, et al. Neoadjuvant immunotherapy leads to major response and low recurrence in localized mismatch repair-deficient colorectal cancer. J Natl Compr Canc Netw 2023;21:60–6.Article PubMed
12. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med 2022;386:2363–76.Article PubMed PMC
13. Trojan J, Stintzing S, Haase O, Koch C, Ziegler P, Demes M, et al. Complete pathological response after neoadjuvant short-course immunotherapy with ipilimumab and nivolumab in locally advanced MSI-H/dMMR rectal cancer. Oncologist 2021;26:e2110–4.Article PubMed PMC PDF

Figure & Data

References

Citations

Citations to this article as recorded by

Liver Transplantation for Non-hepatocellular Carcinoma: The Role of Immune Checkpoint Inhibitors
Pegah Bahrami, Mohammad Al Zein, Ali H. Eid, Amirhossein Sahebkar
Journal of Clinical and Experimental Hepatology.2025; 15(5): 102558. CrossRef

Cite this Article

Cite this Article: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.